U.S. patent number 3,891,623 [Application Number 05/250,045] was granted by the patent office on 1975-06-24 for process for preparing cytidines.
This patent grant is currently assigned to Schering Aktiengesellschaft. Invention is credited to Ulrich Niedballa, Helmut Vorbruggen.
United States Patent |
3,891,623 |
Vorbruggen , et al. |
June 24, 1975 |
Process for preparing cytidines
Abstract
Cytidines of the formula ##SPC1## Wherein the R.sub.1 R.sub.2
N-- is a primary, secondary or tertiary amino group; R.sub.3 is
hydrogen, halogen or lower alkyl of 1 to 6 carbon atoms; X is
oxygen or sulfur; Y is nitrogen or CH; and Z is a free or blocked
sugar residue having cytotoxic, anti-viral, enzyme-inhibiting,
immuno-suppressive, anti-inflammatory, anti-psoriatic,
anti-leucaemic and anti-bacterial activity are produced from the
corresponding 4-trialkylsilyloxyuridines by reaction with ammonia
or a primary or secondary amine followed, if desired, by removal of
blocking groups on the sugar residue.
Inventors: |
Vorbruggen; Helmut (Berlin,
DT), Niedballa; Ulrich (Berlin, DT) |
Assignee: |
Schering Aktiengesellschaft
(Berlin, DT)
|
Family
ID: |
5807376 |
Appl.
No.: |
05/250,045 |
Filed: |
May 3, 1972 |
Foreign Application Priority Data
Current U.S.
Class: |
536/28.5;
536/28.3; 536/28.51; 536/28.52 |
Current CPC
Class: |
C07H
19/06 (20130101); C07H 19/12 (20130101); Y02P
20/55 (20151101) |
Current International
Class: |
C07H
19/12 (20060101); C07H 19/00 (20060101); C07H
19/06 (20060101); C07d 051/52 () |
Field of
Search: |
;260/211.5R |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Brown; Johnnie R.
Attorney, Agent or Firm: Millen, Raptes & White
Claims
What is claimed is:
1. In a process for the preparation of pharmaceutically useful
cytidines of the formula ##SPC5##
wherein R.sub.1 and R.sub.2 are both hydrogen or alkyl of 1 to 6
carbon atoms; or R.sub.1 is hydrogen and R.sub.2 is hydroxyl,
amino, alkyl of 1 to 6 carbon atoms, phenyl or phenyl-lower alkyl
optionally ring substituted with hydroxyl or amino, or amino alkyl
N-substituted with alkyl of 1 to 4 carbon atoms; or R.sub.1 and
R.sub.2 ; together with the N-atom, collectively represent a
heteromonocyclic ring selected from the group consisting of
pyrrolidino, 2-methylpyrrolindino, 2,5-dimethylpyrrolindino,
3-ethylpyrrolindino, piperindino, homopiperidino, morpholino,
imidazolyl, triazolyl, piperazino, indolyl and anilino; R.sub.1 is
hydrogen, halogen or alkyl of 1 to 6 carbon atoms; X is oxygen or
sulfur; Y is nitrogen or CH; and Z is a free or masked
monosaccharide residue, the improvement which comprises reacting a
4-trialkyl-silyloxyuridine derivative of the formula ##SPC6##
wherein Alkyl is of 1 to 3 carbon atoms, Z' is a hydrolyzable
silylated, or hydrolyzable O-acylated masked monosaccharide residue
Z, wherein acyl is lower alkanoyl, benzoyl, p-chlorobenzoyl,
p-nitrobenzoyl, touyl, or benzyl and R.sub.3, X, Y and Z have the
above-indicated meanings, with ammonia or with a primary or
secondary amine of the formula H N R.sub.1 R.sub.2, or with a salt
of said primary or secondary amine in the presence of 1 to 5 moles
of a tertiary amine per mole of amine salt to form said
cytidine.
2. A process according to claim 1, wherein R.sub.1 and R.sub.2 are
both hydrogen or alkyl of 1 to 6 carbon atoms.
3. A process according to claim 2, wherein --N R.sub.1 R.sub.2 is
selected from the group consisting of dimethylamino,
methyl-ethylamino, diethylamino, methyl-n-propylamino,
dipropylamino, diisopropylamino, methylisobutylamino and
di-n-butylamino.
4. A process according to claim 1, wherein R.sub.1 is hydrogen.
5. A process according to claim 1, wherein R.sub.1 and R.sub.2
represent said heteromonocyclic ring.
6. A process according to claim 5, wherein said heteromonocyclic
ring is pyrrolidino, morpholino or piperidino.
7. A process according to claim 1, wherein Alkyl is methyl.
8. A process according to claim 1, wherein Z is a masked
monosaccharide, further comprising hydrolyzing the masking groups
to form the corresponding free sugar.
9. A process according to claim 1, wherein said amine is a primary
amine which is added directly to the 4-trialkyl-silyloxyuridine
derivative.
10. A process according to claim 9, wherein said primary amine is
selected from the group consisting of methylamine, ethylamine,
propylamine, butylamine, benzylamine,
2-(3,4-dihydroxyphenyl)-ethyl-amine, homoveratrylamine,
N,N-dimethylethylenediamine and phenethylamine.
11. A process according to claim 10, wherein said primary amine is
butylamine, benzylamine or phenethylamine.
12. A process according to claim 1, wherein said amine is a
secondary amine.
13. A process according to claim 12, wherein said secondary amine
is added together with a silylating agent to the
4-trialkyl-silyloxyuridine derivative.
14. A process according to claim 12, wherein said secondary amine
is selected from the group consisting of dimethylamine,
diethylamine, pyrrolidine, piperidine, morpholine and
hexamethyleneimine.
15. A process according to claim 14, wherein said secondary amine
is diethylamine, pyrrolidine, piperidine or morpholine.
16. A process according to claim 1, wherein said
4-trialkyl-silyloxyuridine is reacted with a salt of a primary or
secondary amine in the presence of said tertiary amine.
17. A process according to claim 16, wherein said tertiary amine is
selected from the group consisting of trimethylamine,
triethylamine, ethyldiisopropylamine, pyridine and quinoline.
18. A process according to claim 17, wherein said tertiary amine is
triethylamine or ethyldiisopropylamine.
19. A process according to claim 1, wherein said
4-trialkyl-silyloxyuridine is reacted with ammonia formed in situ
by silylating with hexamethylenedisilazine.
20. A process according to claim 1, wherein X is oxygen.
21. A process according to claim 1, wherein Y is nitrogen.
22. A process according to claim 1, wherein R.sub.3 is hydrogen or
methyl.
23. A process according to claim 1, wherein Z is a monosaccharide
selected from the group consisting of ribose, 2-deoxyribose,
glucose, arabinose, aldose, fructose, galactose, galactosamine,
mannose, rhamnose, sorbose, xylose and glucosamine.
24. A process according to claim 23, wherein said monosaccharide is
ribose, deoxyribose, arabinose or glucose.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to an improved process for the preparation
of cytidine and cytidine derivatives.
2. Description of the Prior Art
Cytidines are important antimetabolites and due to their
advantageous biological properties, e.g., enzyme-inhibiting,
immuno-suppressive anti-inflammatory, anti-psoriatic,
anti-leucaemic and anti-bacterial. Cytidines having a free or
blocked ribofuranosyl residue are known in the art and have been
described in Collection Czechoslov. Chem. Commun. 30, 2052 (1965).
Cytidines are generally produced from the readily obtainable
uridines in accordance with the method of Fox et al. described in
J. Am. Chem. Soc. 81, 178 (1959). In this method, the free hydroxy
groups of the sugar residue must first be acylated. The masked
uridines must then be converted, with phosphorus pentasulfide in
pyridine, into the 4-thio-derivatives. These thio-derivatives are
reacted either as such or after conversion into the corresponding
4-thioethers with ammonia or primary or secondary amines to form
the corresponding cytidines. Due to the large number of required
reaction stages, the process is expensive, wasteful and
cumbersome.
OBJECTS OF THE INVENTION
It is accordingly an object of this invention to provide an
improved process for preparing cytidines.
Another object of this invention is to provide new cytidine
derivatives having enzyme-inhibiting, immunosuppressive,
anti-inflammatory, anti-psoriatic and anti-bacterial
activities.
A further object of the this invention is to provide pharmaceutical
compositions containing novel cytidine derivatives as an active
agent.
Other objects of this invention will become apparent to those
skilled in the art from the following discussion of the
invention.
SUMMARY OF THE INVENTION
In one aspect of this invention, cytidines of the Formula I
##SPC2##
wherein R.sub.1 and R.sub.2 are both hydrogen or alkyl of 1 to 6
carbon atoms; or R.sub.1 is hydrogen and R.sub.2 is hydroxyl,
amino, alkyl of 1 to 6 carbon atoms; aryl or aralkyl unsubstituted
or substituted with hydroxyl or amino, aminoalkyl N-substituted
with alkyl of 1 to 4 carbon atoms; or R.sub.1 and R.sub.2, together
with the N-atom, collectively represent a heteromonocyclic ring of
4-7 members containing a total of 1-3 hetero atoms which, in
addition to the nitrogen atom, can be nitrogen, oxygen, or sulfur;
R.sub.3 is hydrogen, halogen, or alkyl of 1 to 6 carbon atoms; X is
oxygen or sulfur; Y is nitrogen or CH; and Z is a free or blocked
sugar residue, are prepared by reacting a 4-trialkylsilyloxyuridine
derivative of Formula II ##SPC3##
wherein Alkyl is alkyl of 1 to 3 carbon atoms, preferably methyl,
Z' is a silylated or acylated sugar residue, and R.sub.3, X, and Y
have the above-indicated meanings, with ammonia or a primary or
secondary amine of the formula HNR.sub.1 R.sub.2, or with a salt of
a primary or secondary amine in the presence of a tertiary amine,
and thereafter optionally hydrolyzing the blocking groups on the
sugar residue.
DETAILED DISCUSSION
It has now been found that uridines silylated in the 4-position can
be reacted directly with ammonia or amines to form corresponding
cytidines. In this reaction, it makes no difference whether the
sugar residue in the uridine is in the free or blocked form, since
any free hydroxy groups in the sugar residue are likewise
silylated, and the silyl groups can be easily split off again after
the reaction.
The 4-trialkylsilyloxyuridines of Formula II used in the process of
this invention are known in the art and can be prepared, for
example, by the method described in the U.S. Pat. Spec. No.
1,118,269.
Particularly suitable as blocking groups are the trimethylsilyl
groups, because they can be readily removed. The starting compounds
silylated on the sugar residue, as set forth in Formula II, are
obtained, e.g., by reacting free uridines with hexamethyldisilazane
(HMDS) in the presence of trimethylchlorosilane or ammonium salts
and optionally in the presence of a tertiary base, such as
pyridine. In this case, the 4-trimethylsilyloxy group and the
blocking groups are introduced simultaneously.
For purposes of the reaction according to the present invention, it
is unnecessary to isolate the starting compounds of Formula II. The
4-trialkylsilyloxyuridine, formed in situ, can be reacted directly
with ammonia or an amine in the reaction solution to form the
corresponding cytidine.
Thus, for example, the intermediate product of Formula II, formed
in the N.sub.1 -glycosidation of 2,4-bis(trimethylsilyl)ated
uracils, instead of being reacted with water to form the uridine,
can be reacted with a compound HNR.sub.1 R.sub.2 to form the
cytidine directly. The details of the reaction depend on the nature
of the compound HNR.sub.1 R.sub.2, as described herein. The
treatment of the silyl compound of Formula II with primary or
secondary amines is generally conducted at -20.degree.C. to
180.degree.C., preferably at 20.degree. to 120.degree.C. When using
a primary or secondary amine in the salt form, the procedure is
effected in the presence of a tertiary amine.
Suitable primary amines include but are not limited to methylamine,
ethylamine, propylamine, butylamine, benzylamine,
2-(3,4-dihydroxyphenyl)-ethyl-amine, homoveratrylamine,
N,N-dimethylethylenediamine, and phenthylamine. Preferred primary
amines are butylamine, benzylamine and phenethylamine.
Suitable secondary amines include but are not limited to
dimethylamine, diethylamine, pyrrolidine, piperidine, morpholine
and hexamethyleneimine. Preferred secondary amines are
diethylamine, pyrrolidine, piperidine and morpholine.
Suitable tertiary amines include but are not limited to
trimethylamine, triethylamine, ethyldiisopropylamine, pyridine and
quinoline. Preferred tertiary amines are triethylamine and
ethyldiisopropylamine.
The tertiary amine is generally used in an amount ranging from 1 to
5 mole, preferably 1 to 2 mole per mole of primary or secondary
amine salt.
Since primary amines will react directly with the silylating agent,
the primary amine must be added after the formation of the silyl
compound of Formula II.
The reaction with ammonia is conducted under elevated pressure of
about 20-50 atmospheres gauge; generally with an NH.sub.3 partial
pressure of 1 to 30 atmospheres gauge. After about 20-80 hours at
0-180.degree. C., the reaction can be terminated. When silylating
with hexamethyldisilazane, free ammonia is liberated and the
silylation and reaction with ammonia can be conducted in a single
stage.
In contrast to the primary amines, the secondary amines exhibit
very low reactivity with the silylating agent. Therefore, the
silylating agent and the secondary amine can be added
simultaneously.
The reaction can take place with an inert solvent, e.g., dioxane,
tetrahydrofuran, dimethylformamide, benzene, toluene, chloroform,
glycol dimethylether, diethylenglycol-dimethylether,
N-methylpyrrolidine, pyridine and triethylamine.
The reaction can be conducted at room temperature or at higher or
lower temperatures, e.g., -20-150.degree. C. Generally, the
reactants are employed in approximately equimolar amounts. However,
it is generally advantageous to employ the amine in a molar excess
in order to obtain as quantitative as possible conversion of the
4-trialkylsilyloxyuridine.
Examples of ##SPC4##
are dimethylamino, methylethylamino, diethylamino,
methyl-n-propylamino, dipropylamino, di-isopropylamino,
methylisobutylamino, di-n-butylamino, pyrrolidino,
2-methylpyrrolidino, 2,5-dimethylpyrrolidino, 3-ethylpyrrolidino,
piperidino, homopiperidino, morpholino, imidazole, triazole,
piperazine, indalyl and anilino, N-lower-alkylanilino, benzylamino,
N-lower-alkyl-benzylamino, o-toluidino, p-toluidino or
N-lower-alkyl-phenylethylamino.
Examples of Z are ribose, 2-deoxyribose, glucose, arabinose,
aldose, fructose, galactose, galactosamine, mannose, rhamnose,
sorbose, xylose, an glucosamine, especially ribose, deoxyribose,
arabinose and glucose.
The hydroxy groups of the sugar residue can be free or blocked,
such as by being O-silylated or O-acylated, as is well-known in the
art. Suitable sugar blocking groups are the hydrolyzable blocking
groups conventionally employed in sugar chemistry, which include
but are not limited to ester and ether groups, e.g., acetyl and
other alkanoyl groups; benzoyl and other aroyl groups, e.g.,
p-chlorobenzoyl, p-nitrobenzoyl, and p-toluyl, and cleavable ether
groups, e.g., a benzyl group.
Compounds which can be prepared according to the process of this
invention, in addition to those shown in the Examples, include:
1-(.beta.-D-glucofuranosyl)-2-oxo-4-pyrrolidino-1,2-dihydro-1,3-diazine;
1-(.beta.-D-arabinofuranosyl)-2-oxo-4-pyrrolidino-1,2-dihydro-1,3-diazine;
2-(2,3,4
arabinopyranosyl)-3-thio-5-pyrrolidino-2,3-dihydro-1,2,4,-triazino;
1-(.beta.-D-ribofuransoyl)-2-oxo-4-piperidino-1,2-dihydro-1,3-diazine.
Other such compounds of this invention are:
2-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyl)-3-thio-5-pyrrolidino-2,3
-dihydro-1,2,4-triazine.
1-(.beta.-D-Ribofuranosyl)-2-oxo-4-pyrrolidino-1,2-dihydro-1,3-diazine.
1-(.beta.-D-Ribofuranosyl)-2-oxo-4-[2-(3,4-dihydroxy-phenyl)-ethylamino]-1,
2-dihydro-1,3-diazine.
1-(.beta.-D-Ribofuranosyl)-2-oxo-4-[2-(N,N-dimethyl-amino)ethylamino]-1,2-d
iazine.
2-(2,3,5-Tri-O-benzoyl-.beta.D-Ribofuranosyl)-3-oxo-5-benzylamino-2,3-dihyd
ro-1,2,4-triazine.
2-(2,3,5-Tri-O-benzoyl-.beta.-D-Ribofuranosyl)-3-oxo-5-pyrrolidino-2,3-dihy
dro-1,2,4-triazine.
2-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyl)-3-thio-5-[(2-phenyl)ethy
lamino]-2,3-dihydro-1,2,4-triazine.
The compounds of this invention can be employed in the same manner
as the known compounds 1-.beta.-arabinofuranosylcytosine [J. Med.
Chem. 15, 116 (1972)] and 1-.beta.-D-ribofuranosyl-5-fluorocytosine
(U.S. Pat. No. 3,002,965).
The compounds of this invention can be employed in mixture with
conventional pharmaceutical excipients. Carrier substances can be
such organic or inorganic substances suitable for parenteral,
enteral, or topical application, and which, of course, do not
deleteriously react with the novel compounds, such as, for example,
water, vegetable oils, polyethylene glycols, gelatin, lactose,
amylose, magnesium stearate, talc, vaseline, cholesterol, etc.
For parenteral application, particularly suitable are solutions,
preferably oily or aqueous solutions, as well as suspensions,
emulsions or implants. Ampoules are convenient unit dosages.
For enteral application, particularly suitable are tablets or
dragees which are also characterized by talc and/or a carbohydrate
carrier or binder or the like, the carbohydrate carrier being
preferably lactose and/or corn starch and/or potato starch. A syrup
or the like can also be used wherein a sweetened vehicle is
employed.
For topical application, viscous to semi-solid forms are used such
as liniments, salves or creams, which are, if desired, sterilized,
or mixed with auxiliary agents, such as preservatives, stabilizers,
or wetting agents, or salts for influencing the osmotic pressure,
or with buffer substances.
The substances of this invention is generally administered to
animals, including, but not limited to, mammals and avians, e.g.,
cattle, cats, dogs, and poultry.
A daily dosage comprises about 100 to 10,000 mg. active compound of
this invention on oral administration and a 5 % greasy ointment on
topical administration. In general, the mg/kg ratio is preferably
about 1 to 100 mg. per kg. of body weight. The dose can be
administered once per day or in increments throughout the day.
Without further elaboration, it is believed that one skilled in the
art can, using the preceding description, utilize the present
invention to its fullest extent. The following preferred specific
embodiments are, therefore, to be construed as merely illustrative,
and not limitative of the remainder of the disclosure in any way
whatsoever.
EXAMPLE 1
1-(.beta.-D-Ribofuranosyl)-2-oxo-4-amino-1,2-dihydro-1,3-diazine
In an autoclave, 4.88 g. of uridine (20 millimols), 50 ml. of HMDS,
and 5 mg. of ammonium chloride were agitated, after saturation with
ammonia, at an interval temperature of 162.degree. C. and under 27
atmospheres gauge for 18 hours. After cooling, the reaction mixture
was once more saturated (30 minutes) with ammonia at room
temperature, and the agitation was continued for another 54 hours
at 162.degree. C./27 atm. gauge. After cooling, the substance was
extracted with methanol. The solvent was removed under vacuum. The
residue was taken up in 400 ml. of methanol and refluxed for 6
hours. The solution was concentrated to dryness under vacuum; the
remaining substance was dissolved in 100 ml. of water and treated
with activated carbon. Upon concentration under vacuum, there
remained 3.9 g. of an almost colorless, amorphous residue. The
substance was crystallized from moist ethanol in the form of
colorless needles.
Yield: 3.42 g. (70.2% of theory); m.p. 230.degree. C. (under
decomposition).
EXAMPLE 2
1-(.beta.-D-Ribofuranosyl)-2-oxo-4-pyrrolidino-1,2-dihydro-1,3-diazine
In a mixture of 50 ml. of absolute pyridine, 10 ml. of HMDS, and
0.1 ml. of trimethylchlorosilane, 5 g. of uridine (20.5 millimols)
was suspended and refluxed for 5 hours at a bath temperature of
140.degree. C.; during this step, the uridine was dissolved. The
solvent was withdrawn under vacuum, the residue was mixed with 5
ml. of absolute pyrrolidine (60.7 mmol) and refluxed for another 20
hours. Then, the mixture was cooled and the solvent eliminated
under vacuum. Residues of pyrrolidine were removed by
codistillation with benzene. The brownish oil was dissolved in
methanol and clarified with activated carbon. After removing the
methanol, the remainder was heated for 45 minutes to 80.degree. C.
with 80% acetic acid. The acetic acid was removed under vacuum, and
the residue was crystallized from ethanol.
Yield: 4.52 g. (74.3% of theory); m.p. 209-211.degree. C.
EXAMPLE 3
1-(.beta.-D-Ribofuranosyl)-2-oxo-4-morpholino-1,2-dihydro-1,3-diazine
In a mixture of 50 ml. of absolute pyridine, 15 ml. of HMDS, and
0.5 ml. of trimethylchlorosilane, 5 g. of uridine (20.5 mmol) was
suspended and refluxed at a bath temperature of 140.degree. C.;
during this step, the uridine was dissolved. After adding 5 ml. of
absolute morpholine (57.4 mmol), the mixture was refluxed another
60 hours. The thin-layer chromatogram showed only traces of the
starting material. The solvent was eliminated under vacuum, and
remainders of morpholine were removed by co-distillation with
toluene. The residue, a brown oil, was heated for 30 minutes at
80.degree. C. with 80% strength acetic acid. Then, the acetic acid
was withdrawn under vacuum. The remainder was dissolved in
methanol, clarified with activated carbon, and subjected to column
chromatography on silica gel. The product was obtained as a
yellowish foam.
Yield: 3.1 g. (46.3% of theory);
C.sub.13 H.sub.19 N.sub.3 O.sub.6 (313.31)
C H N Calculated: 49.83 6.11 13.41 % Found: 49.59 6.24 13.29 %
EXAMPLE 4
1(.beta.-D-Ribofuranosyl)-2-oxo-4-[2-(3,4-dihydroxyphenyl)-ethylamino]-1,2-
dihydro-1,3-diazine.
In a mixture of 25 ml. of absolute pyridine, 80 ml. of HMDS, and
0.5 ml. of trimethylchlorosilane, 5 g. of uridine (20.5 mmol) was
suspended and refluxed at a bath temperature of 140.degree. C. and
was thus dissolved. After the entire amount of uridine had been
dissolved (1 hour), it was heated for another 30 minutes. Then, 3.9
g. of dopamine hydrochloride (20.5 mmol) was added; this substance
was dissolved after 30 minutes. Under further heating, 3.64 ml. of
"Hunig" base (22 mmol) was added, while a dry N.sub.2 stream
bubbled through the solution. The solution became gradually darker.
After refluxing for 43 hours, the thin-layer chromatogram revealed
that a more polar compound had been formed. The solvent was removed
under vacuum, residues of pyridine were removed by codistillation
with toluene. The remainder was heated with 80% acetic acid to
80.degree. C. for 30 minutes. The acetic acid was removed by means
of an oil pump. The residue was subjected to column chromatography
on silica gel. The product was obtained as a yellowish foam.
Yield: 2.8 g. (34.8% of theory). C.sub.17 H.sub.21 N.sub.3 O.sub.7
(379.36)
C H N Calculated: 53.82 5.58 11.08 % Found: 53.57 5.73 10.99 %
EXAMPLE 5
1-(.beta.-D-Ribofuranosyl)-2-oxo-4-[2-(N,N-dimethylamino)-ethylamino]-1,2-d
ihydro-1,3-diazine
5 g. of uridine (20.5 mmol) was suspended in 100 ml. of HMDS. After
the addition of 0.1 ml. of trimethylchlorosilane, the reaction
mixture was heated under reflux for 16 hours, thus causing the
uridine to dissolve. The excess HMDS was removed by a water-jet
aspirator at 110.degree. C. The remainder was mixed with 5 ml. of
absolute N,N-dimethylethylenediamine (56 mmol) and agitated at
120.degree. C. for 65 hours. After cooling, the solution was mixed
with 50 ml. of 80% strength acetic acid and stirred for 17 hours at
room temperature. Then, the mixture was concentrated to dryness
under vacuum. Residual acetic acid was removed by codistillation
with ethanol. The dark-brown residue was subjected to column
chromatography on silica gel with methanol as the eluent. The
product, a yellow foam, was crystallized from ethanol.
Yield: 4.0 g. (62% of theory); m.p. 184.degree.-185.degree. C.
EXAMPLE 6
1-(2-Desoxy-.beta.-D-ribofuranosyl)-2-oxo-4-benzylamino-5-methyl-1,2-dihydr
o-1,3-diazine
In 30 ml. of HMDS, 2.42 g. of thymidine (10 mmol) and 10 mg. of
ammonium chloride were suspended and refluxed for 18 hours. The
excess HMDS was distilled off. The residue was mixed with 1.63 ml.
of absolute benzylamine (15 mmol), and the mixture was stirred for
72 hours at room temperature. Then, the solvent was removed under
vacuum. Any remaining benzylamine was eliminated by codistillation
with ethanol. The residue was taken up in aqueous methanol and
treated with activated carbon. Upon concentration under vacuum, a
yellowish foam remained.
Yield: 1.92 g. (58.2% of theory). C.sub.17 H.sub.21 N.sub.3 O.sub.4
(331.36)
C H N Calculated: 61.62 6.39 12.68 % Found: 61.33 6.52 12.59 %
EXAMPLE 7
1-(2-Desoxy-.beta.-D-ribofuranosyl)-2-oxo-4amino-5-methyl-1,2-dihydro-1,3-d
iazine
In an autoclave, 1.21 g. of thymidine (5 mmol), 20 ml. of HMDS, and
5 mg. of ammonium chloride were agitated, after saturation with
ammonia, at an internal temperature of 162.degree. C. and under 27
atmospheres gauge for 16 hours. After cooling to room temperature,
the mixture was again saturated with ammonia (30 minutes), and the
agitation was continued for another 54 hours at 155.degree. C./27
atm. gauge. After cooling, the substance was flushed out with
methanol. The solvent was removed under vacuum. The dark-brown
residue was taken up in 150 ml. of methanol and refluxed for 6
hours. After concentration under vacuum, the mixture was taken up
in water and treated with activated carbon. Upon concentration
under vacuum, a yellowish residue remained which was crystallized
from absolute ethanol.
Yield: 0.663 g. (55% of theory); m.p. 195.degree. C. (hydrate).
EXAMPLE 8
2-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyl)-3-thio-5-[(2-phenyl)-eth
ylamino]-2,3-dihydro-1,2,4-triazine
2.29 g. of
1-(tetra-O-acetyl-.beta.-D-glucopyranosyl)-2-thio-6-azauracil (5
mmol), 3 ml. of HMDS, and 0.1 ml. of trimethylchlorosilane were
dissolved in 100 ml. of absolute benzene and refluxed for 3 hours.
After cooling to room temperature, the solution was mixed with 1.26
ml. of 2-phenylethylamine (10 mmol). A colorless, crystalline
precipitate was thus obtained. After agitation at room temperature
for 72 hours, the solvent was removed under vacuum. The residue was
crystallized from ethyl acetate.
Yield: 2.25 g. (84% of theory); m.p. 212.degree. C.
EXAMPLE 9
2-(2,3,4,6-Tetra-O-acetyl-.beta.-D-glucopyranosyl)-3-thio-5-pyrrolidino-2,3
-dihydro-1,2,4-triazine
2.29 g. of
1-(tetra-O-acetyl-.beta.-D-glucopyranosyl)-2-thio-6-azauracil (5
mmol), 3 ml. of HMDS, and 0.1 ml. of trimethylchlorosilane were
dissolved in 100 ml. of absolute benzene and refluxed for 3 hours.
After cooling to room temperature, the solution was mixed with 0.83
ml. of absolute pyrrolidine (10 mmol) and agitated at room
temperature for 72 hours. Then, the solvent was removed under
vacuum. The residue was crystallized from methanol.
Yield: 2.12 g. (83% of theory); m.p. 160-162.degree. C.
EXAMPLE 10
2-(2,3,5-Tri-O-benzoyl-.beta.-D-ribofuranosyl)-3-oxo-5-benzylamino-2,3-dihy
dro-1,2,4-triazine
3.0 g. of 6-azauridine tribenzoate (5.38 mmol) was dissolved in 100
ml. of absolute benzene. After adding 3 ml. of HMDS, as well as 0.1
ml. of trimethylchlorosilane, the mixture was refluxed for 3 hours.
After cooling to 70.degree. C. (bath temperature), 1 ml. of
absolute benzylamine (10 mmol) was added thereto, and the mixture
was agitated for 65 hours at room temperature. The solvent was
removed under vacuum, and remaining benzylamine was removed by
codistillation with benzene. The product was crystallized from
isopropanol.
Yield: 2.2 g. (63% of theory); m.p. 178-179.degree. C.
EXAMPLE 11
2-(2,3,5-Tri-O-benzoyl-.beta.-D-ribofuranosyl)-3-oxo-5-pyrrolidino-2,3-dihy
dro-1,2,4-triazine
3.0 g. of 6-azauridine tribenzoate (5.38 mmol), 3 ml. of HMDS, and
0.1 ml. of trimethylchlorosilane were dissolved in 100 ml. of
absolute benzene. The solution was refluxed for 3 hours. Then, 1.0
ml. of absolute pyrrolidine (12.2 mmol) was added thereto, and the
mixture was stirred at room temperature for 15 hours. The solvent
was removed under vacuum, and the residue was crystallized from
ethanol.
Yield: 3.0 g. (91.5% of theory); m.p. 186-187.degree. C.
EXAMPLE 12
2-(2,3,5-Tri-O-benzoyl-.beta.-D-ribofuranosyl)-3-oxo-5-pyrrolidino-2,3-dihy
dro-1,2,4-triazine
2.57 g. of the 2,4-bis(trimethylsilyl) compound of 6-azauracil (10
mmol) and 4.8 g. of 2,3,5-tri-O-benzoylribofuranosyl chloride (10
mmol) were dissolved in 200 ml. of absolute benzene. The solution
was cooled to 10.degree. C. and then 2.0 g. of dried silver
perchlorate (10 mmol), dissolved in 100 ml. of absolute toluene,
was added thereto. White silver chloride precipitated. The reaction
was terminated by one hour of agitation in a flask under the
exclusion of light at room temperature. Under anhydrous conditions,
4.1 ml. of absolute pyrrolidine (43 mmol) was added thereto and the
mixture agitated overnight at room temperature. The brown solution
was filtered off from the solid substance. The residue was washed
with benzene. The combined solutions were washed with sodium
thiosulfate solution and with water. After drying over magnesium
sulfate, the solvent was removed under vacuum. Residues of
pyrrolidine were eliminated by codistillation with toluene. The
residue from the evaporation was a brown oil (6.6 g.). The product
was crystallized from ethanol.
Yield: 2.8 g. (45.9% of theory); m.p. 186-187.degree. C.
EXAMPLE 13
2-(2,3,5-Tri-O-benzoyl-.beta.-D-ribofuranosyl)-3-oxo-5-pyrrolidino-2,3-dihy
dro-1,2,4-triazine
5.04 g. of 1-O-acetyl-2,3,5-tri-O-benzoyl-ribofuranose (10 mmol)
and 11 mmol of the 2,4-bis(trimethylsilyl) compound of 6-azauracil
were dissolved in 150 ml. of absolute 1,2-dichloroethane. After the
addition of 0.84 ml. of tin(IV) chloride (7.6 mmol) in 20 ml. of
absolute 1,2-dichloroethane, the mixture was agitated at room
temperature for 4 hours. Under the exclusion of moisture, 9.8 ml.
of pyrrolidine (120 mmol) was then added. After an initially turbid
mixture, a clear solution was obtained. After 3 hours of agitation
at room temperature, the yellow solution was extracted with ice
water. The organic phase was dried over magnesium sulfate and
concentrated under vacuum. Any remaining pyrrolidine was removed by
codistillation with toluene. The residue from the evaporation was a
brown oil (7.0 g.). The product was crystallized from ethanol.
Yield: 3.5 g. (57.4% of theory); m.p. 186-187.degree. C.
EXAMPLE 14
2-(2,3,5-Tri-O-acetyl-.beta.-D-ribofuranosyl)-3-oxo-5-hydroxylamino-2,3-dih
ydro-1,2,4-triazine
1.86 g. of
2-(2,3,5-tri-O-acetyl-.beta.-D-ribofuranosyl)-6-azauracil (5 mmol),
3 ml. of HMDS, and 0.1 ml. of trimethylchlorosilane were dissolved
in 100 ml. of absolute benzene, and the mixture was refluxed for 3
hours. After cooling to room temperature, the solution was mixed,
under agitation, with 15 ml. of absolute THF wherein 10 mmol of
absolute hydroxylamine was dissolved. The mixture was stirred for
another 72 hours at room temperature and then concentrated to
dryness under vacuum. The residue was crystallized from
ethanol.
Yield: 1.33 g. (68.8% of theory); m.p. 90-92.degree. C.
The preceding examples can be repeated with similar success by
substituting the generically and specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
From the foregoing description, one skilled in the art can easily
ascertain the essential characteristics of this invention, and
without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
* * * * *